Thyrotropin releasing hormone is a tripeptide hormone (L-pyroglutamyl-L-histidyl-L-proline-amide) found in the hypothalamus as well as in other parts of the brain. TRH has multiple biological effects that are mediated through its interactions with various receptors to the peptide. Some, but not all of these actions involve its ability to cause the release of thyrotropin stimulating hormone (TSH), especially from the anterior pituitary tissue of higher mammals. Other properties that TRH has been disclosed to possess include thyroid stimulating, antidepressant and lactation promoting activities [U.S. Pat. No. 3,931,139; Science, 178, 417-418 (1972). Furthermore, its use in the treatment of circulatory shock and/or central nervous system (CNS) ischemic damage [U.S. Pat. No. 4,426,378], as well as in the amelioration of symptoms associated with amyotrophic lateral sclerosis (ALS) [U.S. Pat. No. 4,608,365] and hypertension [U.S. Pat. No. 4,215,110] has been disclosed.
A method of synthesis for one of the thionated TRH analogues encompassed hereby (L-pyroglutamyl-L-histidyl-L-prolinethioamide) was reported by M. Kruszynski in the "Polish Journal of Chemistry", Vol. 60, p. 95 (1986). It was also reported by Kruszynski that the compound exhibited TRH receptor binding affinity as well as a TSH releasing activity matching that of natural TRH. However, there was no disclosure of the compounds ability to highly and selectively bind to TRH receptor sites in the cortex, as compared with its binding to TRH receptor sites in the pituitary. The compound is encompassed by Formula I herein, but not by Formula II.
Several of the thionated TRH analogues encompassed hereby are disclosed by Lankiewicz et al in "Peptides Chemistry, Structure and Biology", Proceedings of the Eleventh American Peptide Symposium, Jul. 9-14, 1989, La Jolla, Calif., USA, p. 976-977 (1990). The compounds are disclosed to possess TSH-releasing activity in vitro. The Lankiewicz et al reference is expressly incorporated by reference.